Delirium complicates 15-53% of major surgery in older adults, resulting in 2-20 fold increased mortality, long term cognitive and functional impairment, and increased healthcare costs. Yet, delirium remains a wholly clinical diagnosis; its pathophysiology remains largely unknown, with no biomarkers to guide its diagnosis or management. Over the past 4.5 years, we conducted the Biomarker Discovery for Delirium project within a National Institute on Aging (NIA) program project that funded the SAGES (Successful Aging after Elective Surgery) study. Using the SAGES plasma biorepository and state-of-the-art approaches, including proteomics, we found that pro-inflammatory cytokines, acute phase reactants, and neuronal injury markers are consistently elevated in delirious patients relative to matched controls. These results support a model for delirium in which a predisposing, systemic pre-inflammatory state results in a dysfunctional response to a stressor (major surgery), leading to blood brain barrier breakdown, microglial activation, neuro-inflammation, neuronal injury and death. Responding to NIA Program Announcement PA-13-168 Secondary analysis of existing data sets and stored biospecimens to address clinical aging research questions, we now propose a new set of Specific Aims with no scientific or budgetary overlap with our P01-funded project. We will leverage specimens from SAGES, and an independent orthopedic cohort, HiPOR (Healthier Postoperative Recovery) that collected and stored both plasma and preoperative cerebrospinal fluid (CSF). We will apply cutting edge systems level Omics methods to define delirium signatures that integrate proteins, lipids, and metabolites from both plasma and CSF. We will seek to confirm and further elucidate the dysfunctional inflammation pathophysiological model described above, and probe additional mechanisms for delirium that might interact with, or be independent of the above pathways. In this context, we propose the following Specific Aims: Aim 1: Define and validate a plasma protein signature for delirium Aim 2: Define plasma lipid and metabolite delirium signatures, integrate with the protein signature, and validate this integrated signature across the SAGES cohort and in the independent HiPOR sample Aim 3: Define an integrated CSF-based protein, lipid, and metabolite signature for delirium. Impact: Our immediate goals are to develop integrated (protein, metabolite, lipid) plasma and CSF-based biomarker signatures for delirium using banked specimens from two cohort studies of older orthopedic patients. We will further elucidate the inflammatory pathway described above and uncover others through the proposed Aims, which will fundamentally advance our knowledge of the pathophysiology of delirium. Ultimately, our goal is to translate our findings to the bedside through improved methods of diagnosis and monitoring of delirium, and though the design of targeted, pathophysiologically based interventions. Therefore, the long term impact of the proposed work will be to transform clinical management of this common, morbid, and costly syndrome.